CAR directs T cell adaptation to bile acids in the small intestine.

Autor: Chen ML; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA., Huang X; Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA., Wang H; Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA., Hegner C; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA., Liu Y; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA., Shang J; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, USA.; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China., Eliason A; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA., Diao H; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA., Park H; X-ray Crystallography Core Facility, The Scripps Research Institute, Jupiter, FL, USA., Frey B; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Wang G; Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA., Mosure SA; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, USA.; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Solt LA; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Kojetin DJ; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, USA.; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Rodriguez-Palacios A; Division of Gastroenterology and Liver Disease, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; University Hospitals Research and Education Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Schady DA; Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA., Weaver CT; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Pipkin ME; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA., Moore DD; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. daviddmoore@berkeley.edu.; Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA. daviddmoore@berkeley.edu., Sundrud MS; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. msundrud@scripps.edu.; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA. msundrud@scripps.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 May; Vol. 593 (7857), pp. 147-151. Date of Electronic Publication: 2021 Apr 07.
DOI: 10.1038/s41586-021-03421-6
Abstrakt: Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine 1 . As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues 2 . Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes 3 , but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4 + T effector (T eff ) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation 4 . Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in T eff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP T eff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1 -/- or Rag2 - / -  mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.
Databáze: MEDLINE
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